Temporal coordination of the transcription factor response to H 2 O 2 stress

• Published in: Nature communications 2024-04, Vol.15 (1), p.3440
• Main Authors: Jose, Elizabeth, March-Steinman, Woody, Wilson, Bryce A, Shanks, Lisa, Parkinson, Chance, Alvarado-Cruz, Isabel, Sweasy, Joann B, Paek, Andrew L
• Format: Article
• Language: English
• Subjects: Animals; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Glucose Oxidase - metabolism; Humans; Hydrogen Peroxide - metabolism; Hydrogen Peroxide - pharmacology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NFATC Transcription Factors - metabolism; Oxidative Stress - drug effects; Peroxiredoxins - genetics; Peroxiredoxins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2041-1723

Oxidative stress from excess H O activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H O , it is unclear whether they are activated at the same H O concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H O activate p53, NRF2 and JUN. Yet under high H O , these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H O is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.